Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2022

Open Access 01-12-2022 | Septicemia | Research

Mitochondrial protective effects caused by the administration of mefenamic acid in sepsis

Authors: Diogo Dominguini, Monique Michels, Leticia B. Wessler, Emilio L. Streck, Tatiana Barichello, Felipe Dal-Pizzol

Published in: Journal of Neuroinflammation | Issue 1/2022

Login to get access

Abstract

The pathophysiology of sepsis may involve the activation of the NOD-type receptor containing the pyrin-3 domain (NLPR-3), mitochondrial and oxidative damages. One of the primary essential oxidation products is 8-oxoguanine (8-oxoG), and its accumulation in mitochondrial DNA (mtDNA) induces cell dysfunction and death, leading to the hypothesis that mtDNA integrity is crucial for maintaining neuronal function during sepsis. In sepsis, the modulation of NLRP-3 activation is critical, and mefenamic acid (MFA) is a potent drug that can reduce inflammasome activity, attenuating the acute cerebral inflammatory process. Thus, this study aimed to evaluate the administration of MFA and its implications for the reduction of inflammatory parameters and mitochondrial damage in animals submitted to polymicrobial sepsis. To test our hypothesis, adult male Wistar rats were submitted to the cecal ligation and perforation (CLP) model for sepsis induction and after receiving an injection of MFA (doses of 10, 30, and 50 mg/kg) or sterile saline (1 mL/kg). At 24 h after sepsis induction, the frontal cortex and hippocampus were dissected to analyze the levels of TNF-α, IL-1β, and IL-18; oxidative damage (thiobarbituric acid reactive substances (TBARS), carbonyl, and DCF-DA (oxidative parameters); protein expression (mitochondrial transcription factor A (TFAM), NLRP-3, 8-oxoG; Bax, Bcl-2 and (ionized calcium-binding adaptor molecule 1 (IBA-1)); and the activity of mitochondrial respiratory chain complexes. It was observed that the septic group in both structures studied showed an increase in proinflammatory cytokines mediated by increased activity in NLRP-3, with more significant oxidative damage and higher production of reactive oxygen species (ROS) by mitochondria. Damage to mtDNA it was also observed with an increase in 8-oxoG levels and lower levels of TFAM and NGF-1. In addition, this group had an increase in pro-apoptotic proteins and IBA-1 positive cells. However, MFA at doses of 30 and 50 mg/kg decreased inflammasome activity, reduced levels of cytokines and oxidative damage, increased bioenergetic efficacy and reduced production of ROS and 8-oxoG, and increased levels of TFAM, NGF-1, Bcl-2, reducing microglial activation. As a result, it is suggested that MFA induces protection in the central nervous system early after the onset of sepsis.
Appendix
Available only for authorised users
Literature
1.
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10.PubMedPubMedCentralCrossRef
2.
Oviedo-Boyso J, Bravo-Patino A, Baizabal-Aguirre VM. Collaborative action of Toll-like and NOD-like receptors as modulators of the inflammatory response to pathogenic bacteria. Mediators Inflamm. 2014;2014: 432785.PubMedPubMedCentralCrossRef
3.
4.
Wang P, Huang J, Li Y, Chang R, Wu H, Lin J, Huang Z. Exogenous carbon monoxide decreases sepsis-induced acute kidney injury and inhibits NLRP3 inflammasome activation in rats. Int J Mol Sci. 2015;16(9):20595–608.PubMedPubMedCentralCrossRef
5.
6.
Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci. 2018;19(10):610–21.PubMedCrossRef
7.
Lee S, Suh GY, Ryter SW, Choi AM. Regulation and function of the nucleotide binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 inflammasome in lung disease. Am J Respir Cell Mol Biol. 2016;54(2):151–60.PubMedPubMedCentralCrossRef
8.
9.
Sui DM, Xie Q, Yi WJ, Gupta S, Yu XY, Li JB, Wang J, Wang JF, Deng XM. Resveratrol Protects against Sepsis-Associated Encephalopathy and Inhibits the NLRP3/IL-1beta Axis in Microglia. Mediators Inflamm. 2016;2016:1045657.PubMedPubMedCentralCrossRef
10.
Picard M, Shirihai OS, Gentil BJ, Burelle Y. Mitochondrial morphology transitions and functions: implications for retrograde signaling? Am J Physiol Regul Integr Comp Physiol. 2013;304(6):R393-406.PubMedPubMedCentralCrossRef
11.
Oka S, Leon J, Sakumi K, Ide T, Kang D, LaFerla FM, Nakabeppu Y. Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease. Sci Rep. 2016;6:37889.PubMedPubMedCentralCrossRef
12.
Luo H, Mu WC, Karki R, Chiang HH, Mohrin M, Shin JJ, Ohkubo R, Ito K, Kanneganti TD, Chen D. Mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome regulates the functional deterioration of hematopoietic stem cell aging. Cell Rep. 2019;26(4):945-954.e944.PubMedPubMedCentralCrossRef
13.
Luo Y, Lu J, Ruan W, Guo X, Chen S. MCC950 attenuated early brain injury by suppressing NLRP3 inflammasome after experimental SAH in rats. Brain Res Bull. 2019;146:320–6.PubMedCrossRef
14.
Long J, Wang Q, He H, Sui X, Lin G, Wang S, Yang J, You P, Luo Y, Wang Y. NLRP3 inflammasome activation is involved in trimethyltin-induced neuroinflammation. Brain Res. 2019;1718:186–93.PubMedCrossRef
15.
Khan MS, Akhter M. Glyceride derivatives as potential prodrugs: synthesis, biological activity and kinetic studies of glyceride derivatives of mefenamic acid. Pharmazie. 2005;60(2):110–4.PubMed
16.
Joo Y, Kim HS, Woo RS, Park CH, Shin KY, Lee JP, Chang KA, Kim S, Suh YH. Mefenamic acid shows neuroprotective effects and improves cognitive impairment in in vitro and in vivo Alzheimer’s disease models. Mol Pharmacol. 2006;69(1):76–84.PubMedCrossRef
17.
Khansari PS, Halliwell RF. Mechanisms underlying neuroprotection by the NSAID mefenamic acid in an experimental model of stroke. Front Neurosci. 2019;13:64.PubMedPubMedCentralCrossRef
18.
Daniels MJ, Rivers-Auty J, Schilling T, Spencer NG, Watremez W, Fasolino V, Booth SJ, White CS, Baldwin AG, Freeman S, et al. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat Commun. 2016;7:12504.PubMedPubMedCentralCrossRef
19.
20.
21.
Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol. 1990;186:421–31.PubMedCrossRef
22.
Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER. Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol. 1990;186:464–78.PubMedCrossRef
23.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75.PubMedCrossRef
24.
Dominguini D, Steckert AV, Abatti MR, Generoso JS, Barichello T, Dal-Pizzol F. The protective effect of PK-11195 on cognitive impairment in rats survived of polymicrobial sepsis. Mol Neurobiol. 2021;58(6):2724–33.PubMedCrossRef
25.
Cassina A, Radi R. Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch Biochem Biophys. 1996;328(2):309–16.PubMedCrossRef
26.
Fischer JC, Ruitenbeek W, Berden JA, Trijbels JM, Veerkamp JH, Stadhouders AM, Sengers RC, Janssen AJ. Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta. 1985;153(1):23–36.PubMedCrossRef
27.
Rustin P, Lebidois J, Chretien D, Bourgeron T, Piechaud JF, Rotig A, Munnich A, Sidi D. Endomyocardial biopsies for early detection of mitochondrial disorders in hypertrophic cardiomyopathies. J Pediatr. 1994;124(2):224–8.PubMedCrossRef
28.
Michels M, Abatti MR, Avila P, Vieira A, Borges H, Carvalho Junior C, Wendhausen D, Gasparotto J, Tiefensee Ribeiro C, Moreira JCF, et al. Characterization and modulation of microglial phenotypes in an animal model of severe sepsis. J Cell Mol Med. 2020;24(1):88–97.PubMedCrossRef
29.
Barichello T, Fortunato JJ, Vitali AM, Feier G, Reinke A, Moreira JC, Quevedo J, Dal-Pizzol F. Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation. Crit Care Med. 2006;34(3):886–9.PubMedCrossRef
30.
Barichello T, Generoso JS, Collodel A, Petronilho F, Dal-Pizzol F. The blood-brain barrier dysfunction in sepsis. Tissue barriers. 2021;9(1):1840912.PubMedCrossRef
31.
Dal-Pizzol F, Rojas HA, dos Santos EM, Vuolo F, Constantino L, Feier G, Pasquali M, Comim CM, Petronilho F, Gelain DP, et al. Matrix metalloproteinase-2 and metalloproteinase-9 activities are associated with blood-brain barrier dysfunction in an animal model of severe sepsis. Mol Neurobiol. 2013;48(1):62–70.PubMedCrossRef
32.
Cauvi DM, Song D, Vazquez DE, Hawisher D, Bermudez JA, Williams MR, Bickler S, Coimbra R, De Maio A. Period of irreversible therapeutic intervention during sepsis correlates with phase of innate immune dysfunction. J Biol Chem. 2012;287(24):19804–15.PubMedPubMedCentralCrossRef
33.
Comim CM, Vilela MC, Constantino LS, Petronilho F, Vuolo F, Lacerda-Queiroz N, Rodrigues DH, da Rocha JL, Teixeira AL, Quevedo J, et al. Traffic of leukocytes and cytokine up-regulation in the central nervous system in sepsis. Intensive Care Med. 2011;37(4):711–8.PubMedCrossRef
34.
Michels M, Abatti M, Vieira A, Avila P, Goulart AI, Borges H, Corneo E, Dominguini D, Barichello T, Dal-Pizzol F. Modulation of microglial phenotypes improves sepsis-induced hippocampus-dependent cognitive impairments and decreases brain inflammation in an animal model of sepsis. Clin Sci. 2020;134(7):765–76.CrossRef
35.
Michels M, Vieira AS, Vuolo F, Zapelini HG, Mendonca B, Mina F, Dominguini D, Steckert A, Schuck PF, Quevedo J, et al. The role of microglia activation in the development of sepsis-induced long-term cognitive impairment. Brain Behav Immun. 2015;43:54–9.PubMedCrossRef
36.
Emmanuilidis K, Weighardt H, Matevossian E, Heidecke CD, Ulm K, Bartels H, Siewert JR, Holzmann B. Differential regulation of systemic IL-18 and IL-12 release during postoperative sepsis: high serum IL-18 as an early predictive indicator of lethal outcome. Shock. 2002;18(4):301–5.PubMedCrossRef
37.
Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD, Latz E. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discovery. 2018;17(8):588–606.PubMedCrossRef
38.
Zhang X, Xu A, Lv J, Zhang Q, Ran Y, Wei C, Wu J. Development of small molecule inhibitors targeting NLRP3 inflammasome pathway for inflammatory diseases. Eur J Med Chem. 2020;185: 111822.PubMedCrossRef
39.
Jiang H, Gong T, Zhou R. The strategies of targeting the NLRP3 inflammasome to treat inflammatory diseases. Adv Immunol. 2020;145:55–93.PubMedCrossRef
40.
Dominguini D, Steckert AV, Michels M, Spies MB, Ritter C, Barichello T, Thompson J, Dal-Pizzol F. The effects of anaesthetics and sedatives on brain inflammation. Neurosci Biobehav Rev. 2021;127:504–13.PubMedCrossRef
41.
Olivieri R, Michels M, Pescador B, Avila P, Abatti M, Cucker L, Burger H, Dominguini D, Quevedo J, Dal-Pizzol F. The additive effect of aging on sepsis-induced cognitive impairment and neuroinflammation. J Neuroimmunol. 2018;314:1–7.PubMedCrossRef
42.
Jang DH, Orloski CJ, Owiredu S, Shofer FS, Greenwood JC, Eckmann DM. Alterations in mitochondrial function in blood cells obtained from patients with sepsis presenting to an emergency department. Shock. 2019;51(5):580–4.PubMedPubMedCentralCrossRef
43.
Rahmel T, Marko B, Nowak H, Bergmann L, Thon P, Rump K, Kreimendahl S, Rassow J, Peters J, Singer M, et al. Mitochondrial dysfunction in sepsis is associated with diminished intramitochondrial TFAM despite its increased cellular expression. Sci Rep. 2020;10(1):21029.PubMedPubMedCentralCrossRef
44.
Comim CM, Cassol OJ Jr, Abreu I, Moraz T, Constantino LS, Vuolo F, Galant LS, de Rochi N, Dos Santos Morais MO, Scaini G, et al. Erythropoietin reverts cognitive impairment and alters the oxidative parameters and energetic metabolism in sepsis animal model. J Neural Transm. 2012;119(11):1267–74.PubMedCrossRef
45.
Michels M, Danieslki LG, Vieira A, Florentino D, Dall’Igna D, Galant L, Sonai B, Vuolo F, Mina F, Pescador B, et al. CD40-CD40 ligand pathway is a major component of acute neuroinflammation and contributes to long-term cognitive dysfunction after sepsis. Mol Med. 2015;21:219–26.PubMedPubMedCentralCrossRef
46.
Deb J, Lakshman TR, Ghosh I, Jana SS, Paine TK. Mechanistic studies of in vitro anti-proliferative and anti-inflammatory activities of the Zn(ii)-NSAID complexes of 1,10-phenanthroline-5,6-dione in MDA-MB-231 cells. Dalton Trans. 2020;49(32):11375–84.PubMedCrossRef
47.
Kim A, Zhong W, Oberley TD. Reversible modulation of cell cycle kinetics in NIH/3T3 mouse fibroblasts by inducible overexpression of mitochondrial manganese superoxide dismutase. Antioxid Redox Signal. 2004;6(3):489–500.PubMedCrossRef
48.
Armagan G, Turunc E, Kanit L, Yalcin A. Neuroprotection by mefenamic acid against D-serine: involvement of oxidative stress, inflammation and apoptosis. Free Radical Res. 2012;46(6):726–39.CrossRef
49.
Acin-Perez R, Enriquez JA. The function of the respiratory supercomplexes: the plasticity model. Biochem Biophys Acta. 2014;1837(4):444–50.PubMed
50.
Chung IC, Chen LC, Tsang NM, Chuang WY, Liao TC, Yuan SN, OuYang CN, Ojcius DM, Wu CC, Chang YS. Mitochondrial oxidative phosphorylation complex regulates NLRP3 inflammasome activation and predicts patient survival in nasopharyngeal carcinoma. MCP. 2020;19(1):142–54.PubMed
51.
52.
Sack MN. Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance. Cardiovasc Res. 2006;72(2):210–9.PubMedCrossRef
53.
Wu YN, Sudarshan VK, Zhu SC, Shao YF, Kim SJ, Zhang YH. Functional interactions between complex I and complex II with nNOS in regulating cardiac mitochondrial activity in sham and hypertensive rat hearts. Pflugers Arch. 2020;472(12):1743–55.PubMedCrossRef
54.
Kim EC, Toyono T, Berlinicke CA, Zack DJ, Jurkunas U, Usui T, Jun AS. Screening and characterization of drugs that protect corneal endothelial cells against unfolded protein response and oxidative stress. Invest Ophthalmol Vis Sci. 2017;58(2):892–900.PubMedPubMedCentralCrossRef
55.
Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401–14.PubMedPubMedCentralCrossRef
56.
Candas D, Li JJ. MnSOD in oxidative stress response-potential regulation via mitochondrial protein influx. Antioxid Redox Signal. 2014;20(10):1599–617.PubMedPubMedCentralCrossRef
57.
Bauerfeld C, Talwar H, Zhang K, Liu Y, Samavati L. MKP-1 modulates mitochondrial transcription factors, oxidative phosphorylation, and glycolysis. ImmunoHorizons. 2020;4(5):245–58.PubMedPubMedCentralCrossRef
58.
Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.PubMedCrossRef
59.
Cividini F, Scott BT, Dai A, Han W, Suarez J, Diaz-Juarez J, Diemer T, Casteel DE, Dillmann WH. O-GlcNAcylation of 8-oxoguanine DNA glycosylase (Ogg1) impairs oxidative mitochondrial DNA lesion repair in diabetic hearts. J Biol Chem. 2016;291(51):26515–28.PubMedPubMedCentralCrossRef
60.
Thomas RR, Khan SM, Portell FR, Smigrodzki RM, Bennett JP Jr. Recombinant human mitochondrial transcription factor A stimulates mitochondrial biogenesis and ATP synthesis, improves motor function after MPTP, reduces oxidative stress and increases survival after endotoxin. Mitochondrion. 2011;11(1):108–18.PubMedCrossRef
61.
Manfredini A, Constantino L, Pinto MC, Michels M, Burger H, Kist LW, Silva MC, Gomes LM, Dominguini D, Steckert A, et al. Mitochondrial dysfunction is associated with long-term cognitive impairment in an animal sepsis model. Clin Sci. 2019;133(18):1993–2004.CrossRef
62.
Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M, Suliman HB, Piantadosi CA, Mayhew TM, Breen P, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med. 2010;182(6):745–51.PubMedPubMedCentralCrossRef
63.
Kraft BD, Chen L, Suliman HB, Piantadosi CA, Welty-Wolf KE. Peripheral blood mononuclear cells demonstrate mitochondrial damage clearance during sepsis. Crit Care Med. 2019;47(5):651–8.PubMedPubMedCentralCrossRef
64.
Supinski GS, Schroder EA, Callahan LA. Mitochondria and critical Illness. Chest. 2020;157(2):310–22.PubMedCrossRef
65.
Comim CM, Cassol OJ Jr, Constantino LS, Felisberto F, Petronilho F, Rezin GT, Scaini G, Daufenbach JF, Streck EL, Quevedo J, et al. Alterations in inflammatory mediators, oxidative stress parameters and energetic metabolism in the brain of sepsis survivor rats. Neurochem Res. 2011;36(2):304–11.PubMedCrossRef
66.
Chen SN, Tan Y, Xiao XC, Li Q, Wu Q, Peng YY, Ren J, Dong ML. Deletion of TLR4 attenuates lipopolysaccharide-induced acute liver injury by inhibiting inflammation and apoptosis. Acta Pharmacol Sin. 2021;42(10):1610–9.PubMedPubMedCentralCrossRef
Metadata
Title
Mitochondrial protective effects caused by the administration of mefenamic acid in sepsis
Authors
Diogo Dominguini
Monique Michels
Leticia B. Wessler
Emilio L. Streck
Tatiana Barichello
Felipe Dal-Pizzol
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2022
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-022-02616-6

Other articles of this Issue 1/2022

Journal of Neuroinflammation 1/2022 Go to the issue

Research

Targeted BRD4 protein degradation by dBET1 ameliorates acute ischemic brain injury and improves functional outcomes associated with reduced neuroinflammation and oxidative stress and preservation of blood–brain barrier integrity

Research

Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

Research

The primary macrophage chemokine, CCL2, is not necessary after a peripheral nerve injury for macrophage recruitment and activation or for conditioning lesion enhanced peripheral regeneration

Research

Metabolomics detects clinically silent neuroinflammatory lesions earlier than neurofilament-light chain in a focal multiple sclerosis animal model

Research

Network alterations underlying anxiety symptoms in early multiple sclerosis

Research

FKBP51 mediates resilience to inflammation-induced anxiety through regulation of glutamic acid decarboxylase 65 expression in mouse hippocampus